Titin Gene (TTN): Description of the Gene Coding for Titin, a Giant Protein of Critical Importance for Myofibrillar Integrity and Elasticity in Vertebrate Striated Muscle

Abstract

Up to 34 350 residues long, titin is the largest protein described to date. The titin locus in human located on chromosome 2q24 expresses up to 100 kb (kilobase) full‐length mRNAs (messenger ribonucleic acid) that are translated into giant polypeptides. Titin is an abundant vertebrate muscle protein, spanning half of the sarcomere. In situ, 1–2 μm long titin polypeptides establish a sarcomeric filament system that is critical for myofibrillar integrity and elasticity. Biomechanically, the titin filament is a fine‐tuned component of the muscle passive force that is regulated trough alternative splicing, posttranslational modifications and protein–protein interactions. A variety of molecular interactions with stress‐regulated ligands position titin centrally in stretch‐dependent signalling in muscle. Consistent with this, a plethora of mutations in the titin filament system cause hereditary myopathies affecting heart, diaphragm and skeletal muscles. In particular, stop codons in one titin allele are a major cause of hereditary dilative cardiomyopathy.

Key Concepts

  • Sarcomeres consist of precisely assembled proteins that together form the basic functional units of striated muscle and that give rise to efficient and finely tuned contraction.
  • In muscle tissues, 12 µm single titin polypeptide chains span half of the sarcomere.
  • The intrasarcomeric filamentous titin protein provides sarcomeres with intrinsic elasticity and couples stretch‐dependent signalling to muscle remodelling.
  • Titin molecule is tailored to physiological requirements of different muscles through alternative splicing, posttranslational modifications and proteinprotein interactions.
  • Consistent with titin's central role in muscle biology, mutations in its gene cause myopathies in heart, skeletal and diaphragm muscle tissues.

Keywords: muscle contraction; myofibrillar elasticity and signaling; sarcomere assembly; dilative cardiomyopathy; muscular dystrophies

Figure 1. (a) Schematic overview of the filament systems in vertebrate striated muscle. Centrally located thick filament (green) consisting mainly of myosin, interacts at both sides of sarcomere with thin filament (red) mainly composed of actin. Thick filament and titin are held together through multiple interactions including C‐protein (red stripes). Titin extends half of the sarcomere: Its N‐terminal region spans the Z‐disc and its C‐terminal region the M‐line, respectively. (b) Schematic model indicating titin's spring segment. The spring extends as the sarcomere is stretched and a restoring force ensues (e.g. as occurs during filling of the heart).
Figure 2. Domain architecture of soleus titin polypeptide (modified from Granzier and Labeit, ). In addition to the 243 Ig/FN3 repeats with structural roles for Z‐disc and thick filament assembly, titin also contains nonrepetitive sequence elements. As these elements include a serine/threonine kinase domain, phosphorylation motifs and calpain protease binding sites, titin appears to have also multiple roles in myofibrillar signal transduction.
Figure 3. Exon–intron structure and domain architecture of the human titin gene (modified from Bang et al., 2001). Titin has a total coding mass of 4200 kDa, which is organised in 363 exons. Numbers indicate TTN missense mutations that are implicated in hereditary dilative cardiomyopathy. P, possible disease‐causing mutation; L, likely disease‐causing mutation. Indicated are also titin domain numbers (top) and exon numbers (bottom). Red rectangle, immunoglobulin‐like domain; white, fibronectin‐type 3 domain; blue, unique sequence; green, z‐repeat domain; yellow, PEVK domain rich in the amino acids P,E,V, and K (i.e. proline, glutamic acid, valine, and lysine); black, titin kinase domain. Mutations in titin's C‐terminal exons 363 and 358 cause the muscular dystrophies TMD (tibialis anterior muscular dystrophy), and a severe form of diaphragm failure (for more information on the respective mutations, see ‘References’ and ‘Further Reading’ sections).
Figure 4. (a) Giant proteins in vertebrate striated muscles. On denaturing 2% polyacrylamide gels, titin bands appear as low mobility species far above the 220 kDa myosin heavy chain (MHC), and the about 800 kDa nebulin band. Please note the mobility difference between the 3700 kD titin from human soleus skeletal muscle, and the 2970 kDa titin from heart muscle (main band in mouse heart and lower titin band in human heart muscle). (b) The different titin polypeptide size classes are caused by the differential processing of titin transcripts by distinct splice pathways (Freiburg et al., ). Titin cDNAs from cardiac muscle (top) and soleus and psoas skeletal muscle (bottom) predict titins that have very different I‐band regions. Identified splice routes are indicated by arrows, black for human and blue for rabbit. Predicted molecular weights of the respective isoforms are given (right).
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References

Bang ML, Centner T, Fornoff F, et al. (2001) The complete gene sequence of titin, expression of an unusual ∼700 kDa titin isoform and its interaction with obscurin identify a novel Z‐line to I‐band linking system. Circulation Research 89: 1065–1072.

Ceyhan‐Birsoy O, Agrawal PB, Hidalgo C, et al. (2013) Recessive truncating titin gene, TTN, mutations presenting as centronuclear myopathy. Neurology 81 (14): 1205–1214.

Clark KA, McElhinny AS, Beckerle MC and Gregorio CC (2002) Striated muscle cytoarchitecture: an intricate web of form and function. Annual Review of Cell and Developmental Biology 18: 637–706.

Dowling JJ (2013) Titin and centronuclear myopathy: The tip of the iceberg for TTN‐ic mutations?. Neurology 81 (14): 1189–1190.

Freiburg A, Trombitas K, Hell W, et al. (2000) Series of exon‐skipping events in titin's elastic spring region as the structural basis for myofibrillar elastic diversity. Circulation Research 86: 1114–1121.

Gramlich M, Michely B, Krohne C, et al. (2009) Stress‐induced dilated cardiomyopathy in a knock‐in mouse model mimicking human titin‐based disease. Journal of Molecular and Cellular Cardiology 47 (3): 352–358.

Gerull B, Gramlich M, Atherton J, et al. (2002) Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy. Nature Genetics 30: 201–204.

Granzier H and Labeit S (2002) Cardiac titin: an adjustable multi‐functional spring. Journal of Physiology 541: 335–342. Review.

Guo W, Schafer S, Greaser ML, et al. (2012) RBM20, a gene for hereditary cardiomyopathy, regulates titin splicing. Nat Med. 18 (5): 766–773.

Hackman P, Vihola A, Haravuori H, et al. (2002) Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal‐muscle protein titin. American Journal of Human Genetics 71: 492–500.

Herman DS, Lam L, Taylor MR, et al. (2012) Truncations of titin causing dilated cardiomyopathy. New England Journal of Medicine 366: 610–628.

Hidalgo C, Hudson B, Bogomolovas J, et al. (2009) PKC phosphorylation of titin's PEVK element: a novel and conserved pathway for modulating myocardial stiffness. Circulation Research 105: 631–638, 617 p following 638.

Krüger M, Kötter S, Grützner A, et al. (2009) Protein kinase G modulates human myocardial passive stiffness by phosphorylation of the titin springs. Circulation Research 104: 87–94.

Labeit S and Kolmerer B (1995) Titins: giant proteins in charge of muscle ultrastructure and elasticity. Science 270: 293–296.

Savarese M, Sarparanta J, Vihola A, et al. (2016) Increasing Role of Titin Mutations in Neuromuscular Disorders. J Neuromuscul Dis. 3 (3): 293–308.

Taylor M, Graw S, Sinagra G, et al. (2011) Genetic variation in titin in arrhythmogenic right ventricular cardiomyopathy–overlap syndromes. Circulation 124 (8): 876–885.

Yamasaki R, Wu Y, McNabb M, et al. (2002) Protein kinase A phosphorylates titin's cardiac‐specific N2B domain and reduces passive tension in rat cardiac myocytes. Circulation Research 90: 1181–1188.

Zou J, Tran D, Baalbaki M, et al. (2015) An internal promoter underlies the difference in disease severity between N‐ and C‐terminal truncation mutations of titin in zebrafish. Elife. 4: e09406.

Further Reading

Buyandelger B, Ng KE, Miocic S, et al. (2011) Genetics of mechanosensation in the heart. Journal of Cardiovascular Translational Research 4: 238–244. Review.

Lange S, Xiang F, Yakovenko A, et al. (2005) The kinase domain of titin controls muscle gene expression and protein turnover. Science 308: 1599–1603.

LeWinter MM and Granzier H (2010) Cardiac titin: a multifunctional giant. Circulation 121: 2137–2145. Review.

Krüger M and Linke WA (2011) The giant protein titin: a regulatory node that integrates myocyte signaling pathways. Journal of Biological Chemistry 286: 9905–9912. Review.

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Labeit, Siegfried, Labeit, Dittmar, and Granzier, Henk(Feb 2018) Titin Gene (TTN): Description of the Gene Coding for Titin, a Giant Protein of Critical Importance for Myofibrillar Integrity and Elasticity in Vertebrate Striated Muscle. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005021.pub3]